Graphene Nanostructure-Based Pharmaceutical Composition for Preventing or Treating Neurodegenerative Diseases

ABSTRACT

The present disclosure relates to a pharmaceutical composition for preventing or treating neurodegenerative diseases, the pharmaceutical composition including a graphene nanostructure as an active ingredient.

TECHNICAL FIELD

The present invention relates to a pharmaceutical composition forpreventing or treating neurodegenerative diseases, the pharmaceuticalcomposition including a graphene nanostructure as an active ingredient.

BACKGROUND

It has been known that protein misfolding causes normal proteins to losetheir function and abnormal proteins to be accumulated in cells andproduce toxicity and thus causes various diseases such as Alzheimer'sdisease, Parkinson's disease, Huntington's chorea, Lou Gehrig's disease,cancer, cystic fibrosis, and type II diabetes. That is, malfunction ofproteostasis causes protein misfolding and its intracellular abnormalaccumulation.

All the causes of neurodegenerative diseases have not yet been found,but it has been well known that aggregation of neuronal proteins is amain cause. Fibrillated proteins are gradually transmitted to adjacentneurons and finally necrose all the neurons in a specific part of thebrain, so that the specific part cannot perform its functions. As forParkinson's disease, the disease progresses while neurons that produce aneurotransmitter called dopamine are gradually necrosed. Sinemet is nowthe most common drug prescribed to Parkinson's disease patients, andSinemet and other Parkinson's disease drugs do not function tofundamentally treat or delay the disease but supply Levodopa (L-DOPA)which is converted into dopamine in neurons to temporally reduce thesymptoms. In the end, as the disease continues to progress, the effectof the drugs decreases, which causes death.

As one of anti-amyloid compounds researched relating to proteinmisfolding, Congo Red has an effect of inhibiting fibril formationcaused by protein misfolding but is highly toxic to the body and cannotfunction to inhibit transition of misfolded proteins and thus delay theprogress of a disease. Further, a conventional drug is formulated into aspecific shape with a uniform size and thus does not have any particularadvantage in the treatment of a disease in terms of entropy.

Accordingly, a lot of studies have been carried out to treat proteinmisfolding (Korean Patent Laid-open Publication No. 10-2009-0019790),but there has been no great achievement about a drug which is not toxicto the body but has an excellent inhibitory activity.

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

Accordingly, the present disclosure provides a pharmaceuticalcomposition for preventing or treating neurodegenerative diseases, thepharmaceutical composition including a graphene nanostructure as anactive ingredient.

However, problems to be solved by the present disclosure are not limitedto the above-described problems. Although not described herein, otherproblems to be solved by the present disclosure can be clearlyunderstood by those skilled in the art from the following descriptions.

Means for Solving the Problems

In accordance with a first aspect of the present disclosure, there isprovided a pharmaceutical composition for preventing or treatingneurodegenerative diseases, the pharmaceutical composition including agraphene nanostructure as an active ingredient.

Effects of the Invention

According to the exemplary embodiments of the present disclosure, thepharmaceutical composition for preventing or treating neurodegenerativediseases, the pharmaceutical composition including a graphenenanostructure as an active ingredient is the first attempt to use agraphene nanostructure for preventing and treating neurodegenerativediseases. The graphene nanostructure is not toxic to the body and notaccumulated in the body, but it has an excellent effect such asinhibiting fibril formation caused by protein misfolding to 80% and iseffective in inhibiting transition of misfolded proteins and thusdelaying the progress of a disease. Further, unlike the conventionaldrug, the graphene nanostructure is not limited to a specific shape andthe graphene nanostructures are different from each other in molecularweight, molecular formula, and shape, which inhibits formation ofcrystals in terms of entropy, and, thus, it is possible to fundamentallytreat a disease. Furthermore, the graphene nanostructure exhibitsfluorescence in a UV-vis range, and it is possible to track movement ofthe graphene nanostructure to act as a drug in the body by appropriatelyregulating the intensity of fluorescence. Also, it is possible to tracka neuronal protein by bonding a material targeting the neuronal proteinto a terminal functional groups of the graphene nanostructure. As such,thee graphene nanostructure may be induced to a place near the neuronalprotein and then a far-infrared laser less damaging a cell may beirradiated, so that fibrillation and aggregation can be inhibited by aphotothermal effect of the graphene nanostructure.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows TEM and AFM images of graphene quantum dots in accordancewith an example of the present disclosure.

FIG. 2 is a graph showing the result of PL analysis on graphene quantumdots in accordance with an example of the present disclosure.

FIG. 3 is a graph showing the result of FT-IR analysis on graphenequantum dots in accordance with an example of the present disclosure.

FIG. 4 is a graph showing the result of Zeta potential measurement ongraphene quantum dots in accordance with an example of the presentdisclosure.

FIG. 5 shows a fibrillation inhibiting effect of a graphenenanostructure in accordance with an example of the present disclosure.

FIG. 6A and FIG. 6B provide (A) images and (B) graphs showing the resultof analysis of a neuron survival rate affected by a graphenenanostructure in accordance with an example of the present disclosure.

FIG. 7A and FIG. 7B provide (A) images and (B) graphs showing the resultof analysis of 8-OHG staining which shows a reactive oxygen speciesgeneration inhibitory activity of a graphene nanostructure in accordancewith an example of the present disclosure.

FIG. 8A and FIG. 8B provide (A) schematic diagrams of a test forconfirming a-syn transition inhibition of a graphene nanostructure inaccordance with an example of the present disclosure and (B) imagesshowing the result thereof.

FIG. 9 shows the result of TEM analysis of fibrillation inhibition of agraphene nanostructure in accordance with an example of the presentdisclosure.

FIG. 10 shows the result of AFM analysis of fibrillation inhibition ofgraphene quantum dots in accordance with an example of the presentdisclosure.

FIG. 11A and FIG. 11B show the result of high-resolution TEM analysis offibrillation inhibition of a graphene nanostructure in accordance withan example of the present disclosure.

FIG. 12 shows the result of BN-PAGE analysis on PFFs after injection ofa graphene nanostructure in accordance with an example of the presentdisclosure.

FIG. 13 provides images showing luminescent characteristics of agraphene nanostructure and Congo Red in accordance with an example ofthe present disclosure.

FIG. 14 is a graph showing photothermal characteristics of a graphenenanostructure in accordance with an example of the present disclosure.

FIG. 15 shows FT-IR spectra of samples prepared in accordance with anexample of the present disclosure.

FIG. 16 shows the result of fluorescence measurement on samples preparedin accordance with an example of the present disclosure.

MODE FOR CARRYING OUT THE INVENTION

Hereinafter, embodiments and examples of the present disclosure will bedescribed in detail with reference to the accompanying drawings so thatthe present disclosure may be readily implemented by those skilled inthe art.

However, it is to be noted that the present disclosure is not limited tothe embodiments and examples but can be embodied in various other ways.In drawings, parts irrelevant to the description are omitted for thesimplicity of explanation, and like reference numerals denote like partsthrough the whole document.

Through the whole document, the term “on” that is used to designate aposition of one element with respect to another element includes both acase that the one element is adjacent to the another element and a casethat any other element exists between these two elements.

Further, through the whole document, the term “comprises or includes”and/or “comprising or including” used in the document means that one ormore other components, steps, operation and/or existence or addition ofelements are not excluded in addition to the described components,steps, operation and/or elements unless context dictates otherwise.Through the whole document, the term “about or approximately” or“substantially” are intended to have meanings close to numerical valuesor ranges specified with an allowable error and intended to preventaccurate or absolute numerical values disclosed for understanding of thepresent disclosure from being illegally or unfairly used by anyunconscionable third party. Through the whole document, the term “stepof” does not mean “step for”.

Through the whole document, the term “combination of” included inMarkush type description means mixture or combination of one or morecomponents, steps, operations and/or elements selected from a groupconsisting of components, steps, operation and/or elements described inMarkush type and thereby means that the disclosure includes one or morecomponents, steps, operations and/or elements selected from the Markushgroup.

Through the whole document, the term “graphene quantum dots (GQDs)”refers to nano-sized fragments of graphene oxides or reduced grapheneoxides.

Through the whole document, the term “graphene” refers to a materialforming a polycyclic aromatic molecule with multiple carbon atomscovalently bonded to each other. The covalently bonded carbon atoms forma six-member ring as a repeating unit, but can further include afive-member ring and/or a seven-member ring.

Through the whole document, the term “graphene oxide” may be abbreviatedas “GO”, and may include a structure in which a functional groupcontaining oxygen such as a carboxyl group, a hydroxyl group, or anepoxy group is bonded onto graphene, but may not be limited thereto.

Through the whole document, the term “reduced graphene oxide” refers tographene oxide decreased in a percentage of oxygen through a reductionprocess and may be abbreviated as “rGO”, but may not be limited thereto.

Hereinafter, the exemplary embodiments of the present disclosure will bedescribed in detail, but the present disclosure may not be limitedthereto.

In accordance with a first aspect of the present disclosure, there isprovided a pharmaceutical composition for preventing or treatingneurodegenerative diseases, the pharmaceutical composition including agraphene nanostructure as an active ingredient.

In accordance with an exemplary embodiment of the present disclosure,the pharmaceutical composition may further include a pharmaceuticallyacceptable carrier or excipient, but may not be limited thereto. Thepharmaceutically acceptable carrier or excipient is not limited as longas it can be used in a pharmaceutical composition, and may include amember selected from the group consisting of, for example, vaseline,lanolin, polyethylene glycol, alcohol, and combinations thereof, but maynot be limited thereto.

In accordance with an exemplary embodiment of the present disclosure,the neurodegenerative diseases are relevant to protein misfolding, andmay include a member selected from the group consisting of, for example,Alzheimer's disease, Parkinson's disease, Huntington's chorea, HIVdementia, stroke, senile systemic amyloidosis, primary systemicamyloidosis, secondary systemic amyloidosis, type II diabetes,amyotrophic amyloidosis, hemodialysis-related amyloidosis, transmissiblespongiform encephalopathy, and multiple sclerosis, but may not belimited thereto.

In accordance with an exemplary embodiment of the present disclosure,the graphene nanostructure may include graphite, graphene, or graphenequantum dots, but may not be limited thereto.

The graphene quantum dots may have a size in the range of, for example,from about 1 nm to about 20 nm, from about 5 nm to about 20 nm, fromabout 10 nm to about 20 nm, from about 15 nm to about 20 nm, from about1 nm to about 15 nm, from about 1 nm to about 10 nm, or from about 1 nmto about 5 nm, but may not be limited thereto.

In accordance with an exemplary embodiment of the present disclosure,the graphene nanostructure may include graphene nanostructures withvarious sizes in the range of from about 1 nm to about 100 nm, forexample, from about 10 nm to about 100 nm, from about 30 nm to about 100nm, from about 50 nm to about 100 nm, from about 70 nm to about 100 nm,from about 90 nm to about 100 nm, from about 1 nm to about 90 nm, fromabout 1 nm to about 70 nm, from about 1 nm to about 50 nm, from about 1nm to about 30 nm, or from about 1 nm to about 10 nm, but may not belimited thereto.

In accordance with an exemplary embodiment of the present disclosure,the graphene nanostructure may inhibit fibril formation caused byprotein misfolding, and also inhibit transition of misfolded proteins,but may not be limited thereto.

In accordance with an exemplary embodiment of the present disclosure,the graphene nanostructure is not accumulated in the body and not toxicto the body.

In accordance with an exemplary embodiment of the present disclosure,the graphene nanostructure may inhibit generation of reactive oxygenspecies in neurons through a mechanism that inhibits mitochondrialdysfunction caused by fibrillated proteins, but may not be limitedthereto.

In accordance with an exemplary embodiment of the present disclosure,the pharmaceutical composition may include a material targeting aneuronal protein, for example, Congo Red as an anti-amyloid material orthioflavin T or S as an amyloid detecting dye, which is bonded to aterminal functional group of the graphene nanostructure, but may not belimited thereto.

The functional group according to the present disclosure may includeoxygen atoms and may be —OH, —COON, or —C═O, but may not be limitedthereto.

In accordance with an exemplary embodiment of the present disclosure,the graphene nanostructure may show a photothermal effect uponirradiation of a far-infrared laser, but may not be limited thereto.

In accordance with an exemplary embodiment of the present disclosure,the pharmaceutical composition of the present disclosure has anadvantage of being able to track a neuronal protein by bonding amaterial targeting the neuronal protein to a terminal functional groupsof the graphene nanostructure. As such, the graphene nanostructure maybe induced to a place near the neuronal protein and then a far-infraredlaser less damaging a cell may be irradiated, so that fibrillation andaggregation can be inhibited by a photothermal effect of the graphenenanostructure.

MODE FOR CARRYING OUT THE INVENTION

Hereinafter, examples of the present disclosure will be described inmore detail, but the scope of the present disclosure is not limitedthereto.

EXAMPLES Preparation Example 1

GQDs were prepared with reference to the article disclosed in NanoLetters 2012 [Nano Lett, 12, 844-849 (2012)]. A carbon fiber was putinto a solution including a mixture of sulfuric acid and nitric acid ata ratio of 3:1 and then heated at 80° C. for 24 hours (thermo-oxidationprocess). After completion of the reaction, the product was purifiedthrough dialysis and vacuum filtration and GQDs in the form of powderwere finally obtained using a Rotovap. The prepared GQDs were particleswith structurally various sizes (about 5 nm to about 20 nm) (FIG. 1).The prepared GQDs had other characteristics such as exhibitingfluorescence under a UV lamp (Emission: 490 nm, and 550 nm) (JASCOFP-8300 Fluorescence Spectrometer) (FIG. 2) and showing a photothermaleffect upon irradiation of 808 nm NIR laser. According to the FT-IRspectrum (Thermo Scientific Nicolet iS 10 FT-IR Spectrometer), acarboxyl group (—COOH) at a terminal of GQDs was observed at 1724 cm⁻¹and an aromatic C═C peak was observed at 1614 cm⁻¹ (FIG. 3). A surfacecharge analyzed from Zeta potential (Malvern Zetasizer Nano ZS) wasshown as about −20 mV (FIG. 4).

Preparation Example 2

A material in which Congo Red as a material targeting a neuronal proteinwas bonded to a terminal functional group of the prepared graphenenanostructure (GQDs) was prepared by a reaction as shown in thefollowing Reaction Formula. Samples 1, 2, and 3 were prepared byapplying different amounts of the Congo Red (100 μg/ml, 250 μg/ml, and500 μg/ml), respectively:

Test Example 1

A fibrillation inhibition effect of a graphene quantum dot wasdetermined using PFFs (pre-formed fibrils) as an alpha-synuclein testmodel. Specifically, fibrils were formed about a week after injection ofthe PFFs into neurons and finally caused necrosis of the neurons.Fibrillation causes phosphorylation of alpha-synuclein and can berecognized by staining as shown in FIG. 5. It was observed that p-a-syn(phosphorylated alpha-synuclei) were dense in response to injection ofPFFs (1 μg/mL) only, but upon injection of GODS (1 μg/mL), the p-a-syn(phosphorylated alpha-synuclei) almost disappeared to the level thatnothing was injected (FIG. 5). As can be seen from FIG. 5, the p-a-synwas reduced to about 80%, which can be practically considered thatfibrillation is almost entirely inhibited. Further, a neuron survivalrate increases by about 20% (FIG. 6B). A neuron survival rate (analyzedby TUNEL screening) in case of injecting GQDs only was higher than acase where only a PBS medium was injected, and, thus, it was confirmedthat the GQDs were not toxic to neurons (FIG. 6A and FIG. 6B). The leftimages of FIG. 6A show TUNNEL screening in which a damaged cell isstained red, the middle images show DAPI staining in which DNA in a cellnucleus is stained blue, and the right images show quantificationthereof.

In a test of whether the graphene nanostructure used herein inhibitsgeneration of reactive oxygen species in neurons through a mechanismthat inhibits mitochondrial dysfunction caused by fibrillated proteins,primarily cultured neurons were stained with 8-OHG(8-oxo-2′-deoxyguanosine as a main product of DNA oxidation) and thenanalyzed (FIG. 7A). As can be seen from FIG. 7A, it was observed thatthe amount of 8-OHG generated by the influence of reactive oxygenspecies remarkably decreased by addition of the graphene nanostructure.A test of mitochondrial dysfunction was confirmed through a basalrespiratory rate and a maximal respiratory rate of a cell, andmitochondrial Complex I activity assay (FIG. 7B). As shown in the graphof FIG. 7B, it was observed that when only PFFs were injected intoneurons, a respiratory rate of mitochondria remarkably decreased andComplex I activity also decreased, and when GQDs and PFFs were injectedinto the neurons, the respiratory rate recovered to a normal level. Theresult of analysis of mitochondrial dysfunction through this test isconsidered important since it corresponds to the neuron survival rateshown in FIG. 6B.

Test Example 2

It is important to simply inhibit fibrillation and increase a neuronsurvival rate, but it is very important to inhibit transition toadjacent neurons in order to treat neurodegenerative diseases and slowthe progress of the neurodegenerative disease. In order to confirm thisfact, a microfluidic device was set up and it was checked which chamberGQDs should be put into in order to inhibit transition. FIG. 8A providesschematic diagrams of the test and FIG. 8B shows the result of the test.In case of C1 (Chamber 1), GQDs were injected into neurons in a firstchamber and in case of C2 (Chamber 2), GQDs were injected into neuronsin a second chamber, and then, transition of fibrillation ofalpha-synuclein to adjacent neurons was observed. In a positive controlgroup including only PFFs without GQDs, it was observed that afibrillated alpha-synuclein was transmitted to Chambers 1 to 3.Secondly, in a device in which GQDs were put into a first neuron,fibrillation was not well developed from the first, and, thus,fibrillation of alpha-synuclein was rarely observed from second andthird neurons. Finally, in a device in which GQDs were put into anintermediate neuron, fibrillation was developed to some degree in thefirst chamber, and the amount of fibrillation was noticeably decreasedin the second neuron where the GQDs were included, and in the lastneuron, it was observed that fibrillation was hardly developed. It isdeemed that a difference in the degree of initial fibrillation betweenthis device and a device which is the positive control group includingonly PFFs without GQDs is an error inherent in the device and caused byincomplete separation of GQDs from each neuron in the device.

Test Example 3

A sampling was performed in the same manner as an intracellularexperiment (1 μg/ml GQDs and 1 μg/ml PFFs were incubated at 37° C. andthen sampled on a silica substrate) and fibrillation inhibition of GQDswas analyzed using an OM (optical microscope), and as a result thereof,when only PFFs were incubated, a large lump expected as an aggregate offibrils was observed (FIG. 9A and FIG. 9B), whereas when PFFs and GQDswere incubated, GQDs and alpha-synuclein oligomers were shown as beingtangled (FIG. 9C and FIG. 9D). In the present result, the total amountof alpha-synuclein and GQDs was excessive and the images were notsufficiently clear to distinctly show the structures thereof, but itcould be seen that the results of the two samples were definitelydifferent from each other.

A sampling was performed in the same manner as the sampling for OManalysis and fibrillation inhibition of GQDs was analyzed using an AFM(atomic force microscope), and as a result thereof, when only PFFs wereincubated, a lewy body formed by aggregation of fibrils and PFFs wasobserved (FIG. 10B), whereas when PFFs and GQDs were incubated, GQDs andalpha-synuclein oligomers were shown as being tangled (FIG. 10D).

A sampling was performed on a TEM (transmission electron microscopy)grid in the same manner as the sampling for OM and AFM analyses, and ananalysis was conducted using a high-resolution transmission electronmicroscope. FIG. 11A shows data obtained by sampling PFFs only on theTEM grid and conducting an analysis. As can be seen from the images, avery thick and long fibril bundle was observed. Meanwhile, in a samplein which GQDs were also included, as shown in the AFM image, GQDs andalpha-synuclein oligomers were shown as being tangled (FIG. 11B).

The images shown in FIG. 9 to FIG. 11 showed a marked difference betweeninjection or non-injection of GQDs with PFFs, but these images wereobtained in a dried state and thus could not show the exact state ofPFFs after injection of GQDs. For more detailed analysis, BN-PAGE (bluenative polyacrylamide gel electrophoresis) was performed, and a resultthereof was surprising (FIG. 12). In FIG. 12, Column 1 is about anegative control group in which only GQDs are included, Columns 2 and 4are about samples in which only PFFs are included, and Columns 3 and 5are about samples in which both PFFs and GQDs are included, and as aresult of gel insertion, it could be seen that when GQDs were injected,a strong band was detected from an area corresponding to alpha-synucleinmonomers (14.46 kDa). This is very important data showing that when GQDsare added to PFFs, fibrillation of PFFs can be inhibited and PFFs arereturned to monomers.

Test Example 4

The GQDs prepared in Preparation Example 1 and a Congo Red solution(control group) were irradiated with infrared rays and fluorescence wasphotographed in the dark, and a result thereof was as shown in FIG. 13.

Further, FIG. 14 shows that when a NIR laser was irradiated, the GQDsshowed a higher photothermal effect than Congo Red or distilled waterand was increased in temperature depending on the concentration of GQDs(500 μg/m L, 250 μg/mL, 100 μg/mL) as the concentration of the GQDs wasincreased.

Test Example 5

A FT-IR analysis and a fluorescence measurement were performed usingvarious samples (GQDs, Sample 1, Sample 2, and Sample 3 prepared inPreparation Examples 1 and 2, and a Congo Red solution as a comparativeexample).

Referring to FIG. 15 showing FT-IR spectra, at a —NH₂ peak 3419 cm⁻¹ ofCongo Red, the peak decreased as the concentration of Congo Redincreased, and even at a carboxyl group (—COOH) peak 1710 cm⁻¹ of aterminal of GQDs, the peak decreased as the concentration of Congo Redincreased, and a peptide bond (—CONH) peak 1660 cm⁻¹ was graduallyformed by conjugation of GQDs and Congo Red, and an aromatic C═C peak1614 cm⁻¹ was maintained in all of the samples as expected.

Meanwhile, fluorescences of the samples depending on a wavelength weremeasured as shown in FIG. 16. Herein, Congo Red was used as a controlgroup, and Sample 1 showed the highest fluorescence peak.

The above description of the present disclosure is provided for thepurpose of illustration, and it would be understood by those skilled inthe art that various changes and modifications may be made withoutchanging technical conception and essential features of the presentdisclosure. Thus, it is clear that the above-described examples areillustrative in all aspects and do not limit the present disclosure. Forexample, each component described to be of a single type can beimplemented in a distributed manner. Likewise, components described tobe distributed can be implemented in a combined manner.

The scope of the present disclosure is defined by the following claimsrather than by the detailed description of the embodiment. It shall beunderstood that all modifications and embodiments conceived from themeaning and scope of the claims and their equivalents are included inthe scope of the present disclosure.

1. A pharmaceutical composition for preventing or treatingneurodegenerative diseases, comprising a graphene nanostructure as anactive ingredient.
 2. The pharmaceutical composition for preventing ortreating neurodegenerative diseases of claim 1, further comprising apharmaceutically acceptable carrier or excipient.
 3. The pharmaceuticalcomposition for preventing or treating neurodegenerative diseases ofclaim 1, wherein the neurodegenerative diseases include a memberselected from the group consisting of Alzheimer's disease, Parkinson'sdisease, Huntington's chorea, HIV dementia, stroke, senile systemicamyloidosis, primary systemic amyloidosis, secondary systemicamyloidosis, type II diabetes, amyotrophic amyloidosis,hemodialysis-related amyloidosis, transmissible spongiformencephalopathy, and multiple sclerosis.
 4. The pharmaceuticalcomposition for preventing or treating neurodegenerative diseases ofclaim 2, wherein the pharmaceutically acceptable carrier or excipientincludes a member selected from the group consisting of vaseline,lanolin, polyethylene glycol, alcohol, and combinations thereof.
 5. Thepharmaceutical composition for preventing or treating neurodegenerativediseases of claim 1, wherein the graphene nanostructure includesgraphite, graphene, or graphene quantum dots.
 6. The pharmaceuticalcomposition for preventing or treating neurodegenerative diseases ofclaim 1, wherein the graphene nanostructure inhibits fibril formationcaused by protein misfolding.
 7. The pharmaceutical composition forpreventing or treating neurodegenerative diseases of claim 1, whereinthe graphene nanostructure inhibits transition of misfolded proteins. 8.The pharmaceutical composition for preventing or treatingneurodegenerative diseases of claim 1, wherein the graphenenanostructure is not accumulated in the body.
 9. The pharmaceuticalcomposition for preventing or treating neurodegenerative diseases ofclaim 1, wherein a terminal functional group of the graphenenanostructure is bonded to a material targeting a neuronal protein. 10.The pharmaceutical composition for preventing or treatingneurodegenerative diseases of claim 1, wherein the graphenenanostructure shows a photothermal effect upon irradiation of afar-infrared laser.